Substituted 2-imidazolinones



United States Patent ()fiice 3,355,457 Patented Nov. 28, 1967 Thisinvention relates to new organic compounds. More particularly, theinvention relates to new Z-imidazolinones and intermediates thereof andto processes of preparing the same.

The novel compounds of this invention may be illustrated by thefollowing formula:

wherein R, R and R are members of the group consisting of hydrogen,halogen, lower alkyl, lower alkoxy, nitro and trifluoromethyl and R andR when on adjacent carbon atoms may represent the methylenedioxy group;R and R, are members of the, group consisting of lower -alkyl,'mononuclear ar(lower)alkyl, and when taken together with the nitrogenare pyrrolidino, lower alkylpyrrolidino, piperidino, loweralkylpiperidino, morpholino, lower 'alkylmorpholino,hexarnethyleneimino, lower alkylpiperazinyl and phenylpiperazinyl; n isan integer from 2 to 4 and acid addition salts.

The free bases of this invention may be liquids or solids at roomtemperature. They are, in general, relatively insoluble in Water, butsoluble in most organic solvents such as lower alkyl alcoholsand esters,acetone, chloroform, and the like. These compounds form acid additionsalts with acids such as hydrochloric acid, sulfuric acid, maleic acid,fumaric acid and the like; and such salts are, in general, soluble inwater, methanol, and ethanol, but relatively insoluble in benzene,ether, petroleum ether and the like.

The compounds of this invention may be prepared by the following methodwhich involves the cyclization of an appropriatel-(tert-aminoalkyl)-3-phenylureidoacetaldehyde 'diethylacetalderivative.

The cyclization occurs easily and in good yield when the derivative ofthe. appropriate l-(tert-aminoalkyl)-3-phen ylureidoacetaldehydediethylacetal is heated at 80 C. .with ethanolic hydrochloric acid forabout two to four hours. However, the, reaction is not limited to thisacid alone and cyclization also may be carried out with other acids andsolvents. Further the reaction is not limited to the time andtemperature specified which represents the optimum conditions.

The present compounds are valuable chemical intermediates for thepreparation of the saturated analogs described and claimed in ourcopending application Ser. No. 227,078 filed Sept. 28, 1962, now US.Patent 3,196,152.

The Z-imidazolinones are chemical intermediates for the preparation of2-imidazolidinone derivatives, compounds which have potent tranquilizeractivity and are prepared by the method illustrated in the followingequation:

wherein R, R R R R and n are as hereinbefore described. This conversionmay be carried out by catalytic hydrogenation using palladium, platinum,nickel or other metal catalysts. The reaction may also be carried out byelectrolytic reduction or by use of other suitable reducing agents suchas diborane and the like. The desired products are easily isolated asthe free bases or as suitable salts.

Among the compounds of the present invention 1-(2-dimethylaminoethyl)-3-pnenyl-2-imidazolinone; 1-(2-dimethylarninoethyl)3 (3,4-methylenedioxyphenyl) 2- imidazolinone; 1 (Z-dimethylaminoethyl)3 (m-nitrophenyD-Z-imidazolinone and 1-(m-chlorophenyl)-3-(3-dimethylaminopropyl)-2-irnidazolinone have been found active against thephenyl-p-quinone writhing syndrome in mice. The testing procedure usedwas that reported by Vander Wender and Margolin, Fed. Proc. 15, 494(1956) as a method for testing analgesics which has been modified bySiegmund et al., Proc. Soc. Exp. Biol. Med. 95, 729 (1957). Among theknown analgesics which exhibit etficacy in blocking this response are,for example, acetylsalicyclic acid, phenacetin, phenyl butazone,meperidine, morphine and the like.

The following specific examples illustrate the preparation ofrepresentative compounds of the present invention. Parts are by weightunless otherwise indicated.

EXAMPLE 1 Preparation of 1-(Z-dimethylaminoethyl)-3-phenylureidoacetaldehyzie diethylacetal A solution of 10.6 parts ofdimethylaminoethylaminoacetaldehyde diethylacetal' in 25 parts of hexaneis added dropwise with stirring to a solution of 6.2" parts ofphenylisocyanate in 25 parts of hexane. The mixture is stirred withoutexternal heat for one hour and then heated at reflux temperature for onehalf hour. The solvent is removed by distillation under reducedpressure. The viscous oil which remains is essentially pureI-(Z-dimethylaminoethyl)-3-phenylureidoacetaldehyde diethylacetal, andis obtained in nearly quantitative yield, 11 1.5128.

EXAMPLE 2' Preparation of S-(m-chlorophenyl) -1-(2-dimethylamin0- ethyl)ureidoacetaldehyde diethylacetal Following the procedure of Example 1and reacting dimethylaminoethylaminoacetaldehyde diethylacetal withm-chloropnenylisocyanate the product, 3-(m-chlorophenyl)-1-(2-dimethylaminoethy1 )ureidoacetaldehyde diethylacetal, n 1.5168 isobtained.

EXAMPLE 3 Preparation of 3- (p-chlorophenyl) -1-(2-dimethylaminoethyl)ureidoacetaldehyde diethylacetal Using the procedure of Example 1 andreacting dimethylaminoethylaminoacetaldehyde diethylacetal withp-chlorophenyl isocyanate the product,3-(p-chlorophenyl)-1-(2-dimethylaminoethyl)ureidoacetaldehydediethylacetal, 12 1.5228, is obtained.

EXAMPLE 4 Preparation of I-(Z-dimethylaminoethyl)-3-(p-flaorophenyl)ureidoacetaldehyde diethylacetal When the procedure ofExample 1 is used and dimethylaminoethylaminoacetaldehyde diethylacetalis reacted with p-fluorophenylisocyanate, the product,1-(2-dimethylaminoethyl -3 -(p-fluoropheny1)ureidoacetaldehydediethylacetal, is obtained.

EXAMPLE 5 Preparation of 1-(Z-dimethylaminoethyl) -3-(m-nitrophenyl)-ureidoacetaldehyde diethylacetal Using the procedure described inExample 1 and reacting dimethylaminoethylaminoacetaldehyde diethylacetaland m-nitrophenylisocyanate the product I-(Z-dimethylaminoethyl) 3(m-nitrophenyl)ureidoacetaldehyde diethylacetal, 12 1.5289, is obtained.

EXAMPLE 6 Preparation of1-(Z-dirnethylaminoethyl)-3-(3,4-dimethoxyphenyl)ureidoacetaldehydediethylacetal Using the procedure of Example 1 and reactingdimethylaminoethylaminoacetaldehyde diethylacetal with3,4-dimethoxyphenylisocyanate the product 1 (2 dimethylaminoethyl)-3(3,4 dimethoxyphenyl)ureidoacetaldehyde diethylacetal, is obtained.

EXAMPLE 7 Preparation of 1 (Z-dimethylaminoethyl)-3-(3,4,5-trimethoxyphenyl) ureidoacetaldehyde diethylacetal Followingthe procedure outlined in Example 1 and reactingdimethylaminoethylaminoacetaldehyde diethylacetal with3,4,S-trimethoxyphenylisocyanate the product 1-(2-dimethylaminoethyD-3(3,4,5 trimethoxyphenyl) ureidoacetaldehyde diethylacetal, n 1.5225, isobtained.

EXAMPLE 8 Preparation ofI-(Z-dimethylaminoethyl)-3-(3,4-methylenedioxyphenyl) areidoacetaldehydediethylacetal When dimethylaminoethylaminoacetaldehyde diethylacetal isreacted with 3,4-methylenedioxyphenylisocyanate by the procedureoutlined in Example 1 the product obtained is1-(2-dimethylaminoethyl)-3-(3,4 methylenedioxyphenyl)ureidoacetaldehydediethylacetal.

EXAMPLE 9 Preparation of 3- (m-chlorophenyl) -1- (3-dimethylamz'n'opropyl) -ureidoacetaldehyde diethylacetal Using theprocedure of Example 1 and reacting dimethylaminopropylaminoacetaldehydediethylacetal and mchlorophenylisocyanate the following product isobtained, 3-(m-chlorophenyl)-1-(3 dimethylaminopropyDureidoacetaldehydediethylacetal, n 1.5190.

EXAMPLE 10 Preparation of 3-(m chlorophenyl) -1- (Z-dimethylaminoethyl)-2-imz'dazolin0ne hydrochloride filtered oflF. This product is furtherpurified by recrystallization from ethyl acetate by addition of hexane.Pure 3 (m-chlorophenyl)-1-(2 dimethylaminoethyl) 2 imidazolinone isrecovered, melting point 6l-62 C.

The hydrochloride salt, melting point l71 C., is obtained when the freebase is dissolved in benzene or other and reacted with ethanolichydrogen chloride. Final purification is by crystallization from ethanolor ethanol by addition of ether.

EXAMPLE 11 Preparation of 1(Z-dimethylaminoethyl)-3-(mmethylphenyl)-2-imidazolinone When l-(2-diethylaminoethyl)-3 (m-methylphenyl)ureidoacetaldehyde diethylacetal, prepared as described hereinbefore, iscyclized by the procedure of Example 10,I-(Z-diethylaminoethyl)-3-(m-methylphenyl)-2 imidazolinone is obtained.

EXAMPLE 12 Preparation of 3-(m-bromophenyl)-1-(2-pyrrolidinoethyl)-Z-imidazolinone If 3-(m-bromophenyl)-1-(2-pyrrolidinoethyl)ureidoacetaldehyde diethylacetal, prepared as described hereinbefore, isheated with ethanolic hydrogen chloride as described in Example 10,3-(m-bromophenyl)-1-(2-pyrrolidinoethyl)-2-irnidazolinone is obtained,

EXAMPLE 13 Preparation of I-(Z-dimethylarninoethyl)-3-phenyl-2-imidazolinone hydrochloride Following the procedure of Example 10 andcyclizing the compound1-(2-dimethylaminoethyl)-3-phenylureidoacetaldehyde diethylacetal(Example 1) the following compound is obtained,1-(2-dimethylaminoethyl)-3-phenyl-2-imidazolinone hydrochloride, meltingpoint 173- 174 C.

EXAMPLE 14 Preparation of 3- (o-chlorophenyl) -1- (Z-piperidz'noethyl)Z-imidazolinone Using the procedure of Example 10 and reacting 3-(0-chlorophenyD-l-(Z piperidinoethyl)ureidoacetaldehyde diethylacetal,prepared as described hereinbefore, 3-(0- chlorophenyl)-1(2-piperidinoethyl)-2 imidazolinone is obtained.

EXAMPLE 15 Preparation of3-(p-chlorophenyl)-1-(2-dimethylaminoethyl)-2-imidazolinonehydrochloride When the procedure of Example 10 is followed and thestarting material is 3-(p-chloropheny1)-l-(2dimethylaminoethyl)ureidoacetaldehyde diethylacetal (Example 3) theproduct resulting is3-(p-chlorophenyl)-l-(2-dimethylaminoethyl)-2-imidazolinonehydrochloride, melting point 203 -205 C.

EXAMPLE 16 Preparation of 1-(Z-morpholinoethyl)-3-(m-trifluormmethylphenyl)-2-imidaz0linone When 1-(2-morpholinoethyl) 3(m-trifluoromethylphenyl)ureidoacetaldehyde diethylacetal, prepared asdescribed hereinbefore, is cyclized by the procedure of Example 10,1-(2-morpholinoethyl)-3 (m trifluoromethylphenyl)-2-imidazolinone isobtained.

EXAMPLE 17 Preparation of3-(m-chlorophenyl)-1-(Z-hexamethyleneiminoethyl)-2-imidaz0linone If3-(m-chlorophenyl)-1(2 hexamethyleneiminoethyl) ureidoacetaldhydediethylacetal, prepared as described hereinbefore, is heated withethanolic hydrogen chloride as described in Example 10,3-(m-chlorophenyD-l-(2- hexamethyleneiminoethyl)-2-imidazolinone isobtained.

EXAMPLE 18 Preparation ofI-(Z-dimethylaminoethyl)-3-(p-flaorophenyl)-2-im-idazolin0nehydrochloride Using the method described in Example and the compoundl-(2-dimethylaminoethyl)-3-(p-fluorophenyl)- ureidoacetaldehydediethylacetal (Example 4) the follow ing product is obtained,l-(2-dimethylaminoethyl)-3-(pfluorophenyl) 2 imidazolinonehydrochloride, melting point 203-204 C.

EXAMPLE 19 Preparation of 1- (m-chlorophenyl) -3- [2- (4-m ethyl-I-piperazinyl) ethyl]-2-imidazolinone Using the procedure of Example 10and reacting 3-(mchlorophenyl)-1-[2 (4 methyl 1 piperazinyl) ethyl]ureidoacetaldehyde diethylacetal, prepared as described hereinbefore,1-(m-chlorophenyl)-3-[2-(4amethyl-1-piperazinyl) ethyl] -2-imidazolinoneis obtained.

EXAMPLE 20 Preparation of I-(m-chlorophenyl) -3-[2- l-phenyl-I-piperazinyl) ethyl] -2-imidazolinone Following the procedure ofExample 10 and cyclizing compound 3(m-chlorophenyl)-1-[2-(4-phenyl-1-piperazinyl)-ethyl]ureidoacetaldehydediethylacetal, prepared as described hereinbefore, 1(m-chlorophenyl)-3-[2-(4- phenyl-l-piperazinyl) ethyl] -2-imidazol inoneis obtained.

EXAMPLE 21 Preparation of 1-(Z-dimethylaminoethyl)-3-(m nitrophenyl)-2-imidazolinone hydrochloride Following the procedure outlined inExample 10 and using as starting materialI-(Z-dimethylaminoethyl)-3-(mnitrophenyl)ureidoacetaldehydediethylacetal (Example 5) the product obtained isI-(Z-dimethylaminoethyl)-3- (m-nitrophenyl)-2-imidazolinonehydrochloride, melting point 213215 C. I

EXAMPLE 22 Preparation of 1-(m-chlorophenyl)-3-[Z-(methylphenethylamino) ethyl] -2-imitlazolinone When the procedure ofExample 10 is obtained and the starting material is3-(m-ehlorophenyl)-l-[2-(methylphenethylamino)ethylJureidoacetaldehydediethylacetal, prepared as hereinbefore described, the product resultingis 1 (m chlorophenyl) -3- [Z-(methylphenethylamino)ethyl]-2-imidazolinone.

EXAMPLE 23 Preparation of 1- (m-chlorophenyl) -3- [2-(Z-methylpyrrolidino) -ethyl] -2-imidazolinone Using the methoddescribed in Example 10 and the starting material3-(m-chlorophenyl)-1[2-(2-methylpyrrolidino)ethyl]ureidoacetaldehydediethylacetal, prepared as herein-before described, the compound1-(m-chlorophenyl) 3 [2 (2 methylpyrrolidino)ethyl] 2 imidazolinone isobtained.

EXAMPLE 24 Preparation of1-(3,4-dimethoxyphenyl)-3-(2-dirnethylaminoethyl) -2-imidazolinonehydrochloride When the procedure of Example 10 is used and the startingmaterial is1-(Z-dimethylaminoethyl)-3-(3,4-dimethoxyphenyl)ureidoacetaldehydediethylacetal (Example 6) the product obtained is1-(3,4-dimethoxyphenyl)-3-(2-dimethylaminoethyl) -2-imidazolinonehydrochloride, melting point 169170 C.

EXAMPLE 25 Preparation ofJ-(m-chlorophenyl)-3-[2-(2,6-a'imethylmorpholino)-ethyl]-2-imidazolinoneWhen the procedure of Example 10 is used and the 6 starting material is3-(m-chlorophenyl)-1-[2-(2,6-dimethylrnorpholino)ethyl]ureidoacetaldehyde diethylacetal, prepared as hereinbeforedescribed 1-(m-chlorophenyl)-3-[2-(2,6-dimethylmorpholino)ethyl]-2-imidazolinone is obtained.

EXAMPLE 26 Preparation of 1- (m-chlorophenyl) -3- [2- (Z-methylpiperidino) -ethyl] -2-imidazolinone Following the procedure of Example 10and using as starting material, 3(m-chlorophenyl)-1-[2-(2-methylpiperidino)ethyl]ureidoacetaldehydediethylacetal, prepared as described hereinbefore, 1-(m-chlorophenyl)-3-[2-(2-methylpiperidino)ethyl] 2 imidazolinone is obtained.

EXAMPLE 27 Preparation of 1 (Z-dimethy laminoethyl -3- (3,4,5trimethoxyphenyl) -2-imidazolinone Using the procedure of Example 10 andthe starting material 1(Z-dimethylaminoethyl)-3-(3,4,5-trimethoxyphenyl) ureidoacetaldehydediethylacetal (Example 7) the product obtained is1-(2-dimethylaminoethyl) -3-(3,4,S-trimethoxyphenyl)-2-imidazolinone,which in the form of its maleate salt has a melting point of 122-124 C.

EXAMPLE 28 Preparation of Z-(m-chlorophenyl) -3-(2-dimethylaminoethyl)-2-imidazolidinone A mixture of 3.0 parts of1-(m-chlorpheny1)-3-(2-dimethylamin'oethyl)'-2-imidazolinonehydrochloride, parts of 90% ethanol, and 1 part of 10%palladium-oncarbon catalyst is stirred in a hydrogenator until 250 partsby volume of hydrogen is absorbed. The mixture is filtered and thesolvent is removed. The residue is mixed with 4.0 parts of 5 N-sodiumhydroxide and the organic product is extracted into ether. The etherlayer is concentrated and the residue is chromatographed in order .toremove pure 1-(m-chlorophenyl)-3-(2-dimethy1aminoethyl) -2-imidazolidinone.

EXAMPLE 29 Preparation of 1- (Z-dimethylaminoethyl) -3-(3,4-methylenedioxyphenyl) -2-imidazolinone hydrochloride When theprocedure of Example 10 is used and the starting material is 1(Z-dirnethylaminoethyl)-3-(3,4- methylenedioxyphenyl)ureidoacetaldehydediethylacetal (Example 8) the product obtained isl-(2-dimethylamiuoethyl) -3- 3,4-methylenedioxyphenyl) -2-imidazolinonehydrochloride, melting point 2l8220 C.

EXAMPLE 30 Preparation of 1- (m-chlorophenyl) -3- (Z-dimethylaminoethyl) -2-imidazolidinone A solution of 1.33 parts of1-(m-chlorophenyD-3-(2- dimethylaminoethyl)-2-imidazolinone in 30 partsof diglyme is cooled and mixed with 10 ml. of 1 M boron hydride intetrahydrofuran. The mixture is left at room temperature for one hourand heated in an oil bath at '180 for two hours. The reaction mixture iscooled, 10 ml. of propionic acid is added and the mixture is againheated for two hours in an oil bath at 170180. After cooling, thesolvent is removed under reduced pressure and the residue is madestrongly alkaline with dilute sodium hydroxide solution. The organicproduct is extracted into ether and chromatographed. Pure l-(mchlorophenyl)-3-(2-di1nethyla.minoethyl) 2 imidazolidinone is obtained.

EXAMPLE 31 Preparation of 1(m.-Chl0r0phenyl) -3-(3-dimethylaminopropyl)-2-imidazolinone hydrochloride Using the procedure of Example 10 andstarting ma- 7 terial l-(3-dimethylarninopropyl) 3- (mchlorophenyl)ureidoacetaldehyde diethylacetal (Example 9) the productobtained is l-(m-chlorophenyl)-3-(3 dimethylaminopropyl) 2 imidazolinonehydrochloride, melting point 138140 C. Y

EXAMPLE 32 Preparation of 1-(Z-dimethylaminoethyl)-3-phenyl-Z-imidazolidinone hydrochloride EXAMPLE 33 Preparation of1-(m-aminophenyl)-3-(Z-dimelhylaminoethyl)-2-imidazolidinonehydrochloride Following the procedure of Example 32 and using asstarting material l-(2dimethylaminoethyl)-3-(m-nitrophenyl)-2-imidazolinone hydrochloride(Example 21) the product, l-(m-aminophenyD-B-(Z dimethylaminoethyl)-Z-imidazolidinone hydrochloride, melting point 197 -199 C., is obtained.

EXAMPLE 34 Preparation of1-(3,4-dimethoxyphenyl)-3-(2-dimethylaminoethyl)-2-imidaz0lidinonehydrochloride When the procedure of Example 32 is followed and thestarting material is 1-(3,4-dimethoxyphenyl) 3 (2-dimethylaminoethyD-Zimidazolinone hydrochloride (Example 24) the product obtained isl-(3,4-dimethoxyphenyl)-3-(2 dimethylaminoethyl)-2-imidazolidinonehydrochloride, melting point 177-179 C.

EXAMPLE 35 Preparation ofJ-(Z-dimethylaminoezhyl)-3-(3,4,5-trimethoxyphenyl)-2-imidazolidinonehydrochloride When the procedure of Example 32 is followed and thestarting material is 1-(2-dimethylaminoethyl)-3-(3,4,5-trimethoxyphenyl) 2 imidazolinone (Example 16) the product obtained is1-(Z-dimethylaminoethyl)-3-(3,4,5- trimethoxyphenyl)-2-imidazo1idinonehydrochloride, melting point 200201 C.

EXAMPLE 36 Preparation of 1-(Z-dimethylaminoethyl)-3-(3,4-methylened'ioxyphenyl)-2-im.idaz0lia'inone hydrochloride Usingthe procedure described in Example 32 and starting with the compound1-(2-dimethylaminoethyl)-3-(3,4- methylenedioxyphenyl)-2 imidazolidinonehydrochloride (Example 17) the product obtained is1-(2-dirnethylaminoethyl)-3-(3,4-methylenedioxyphenyl) 2 imidazolidinonehydrochloride, melting point 235 -237 C.

8 EXAMPLE 37 Preparation of I-(m-chlorophenyl)-3-(4-dimethylaminobutyl)-2-imidaz0linone When the procedure of Example. 10 is used and thestarting material is B-(m-chlorophenyl) 1(4-dimethylaminobutyl)ureidoacetaldehyde diethylacetal, the product isl-(m-chlorophenyl) 3 (4 dimethylaminobutyl)-2 imidazolinone.

We claim:

1. A compound selected from those of the formula:

N o.rn.N N-@ 7 R4 r m wherein R, R and R are members of the groupconsisting of hydrogen, halogen, lower alkyl, lower alkoxy, nitro andtrifiuoromethyl and R and R when on adjacent carbon atoms may representthe methylenedioxy group; R and R are members of the group consisting oflower alkyl, phenyl(lower)-alkyl, and when taken together with thenitrogen are pyrrolidino, lower alkylpyrrolidino, piperidino, loweralkylpiperidino, morpholino, lower alkyl morpholino,hexamethyleneirnino, lower alkylpiperazinyl and phenylpiperazinyl; n isan integer from 2 to 4 and an acid addition salt thereof. 7 2. Acompound according to claim 1 in which R is halogen, R and R arehydrogen, R and R are lower alkyl and n is 2.

3. The compound3-(m-chlorophenyl)-l-(2-dirnethylaminoethyl)-2-imidazolinone.

4. The compound I-(Z-dimethylaminoethyl)-3-phenyl- 2-imidazolinone.

5. The compound 3-(p-chlorophenyl)-1-(2-dimethylaminoethyl)-2-imidazolinone.

6. The compound I-(Z-dimethylaminoethyl) 3 (pfluorophenyl)-2-imidazolinone.

7. The compound l-(2-dimethylaminoethyl) 3 (mnitrophenyl-2-imidazolinone.

8. The compound 1-(3,4-dimethoxypheny1) 3 (2-dimethylaminoethyl)-2-imidazolinone.

9. The compound 1-(2-dimethylaminoethyl)-3-(3,4,5-trimethoxyphenyl)-2-imidazolinone.

10. The compound 1-(2 dimethylaminoethyl)-3-(3,4- methylenedioxyphenyl-2-imidazolinone.

11. The compound l-(m-chlorophenyl)-3-(3-dimethylaminopropyl) -2-imidazolinone.

12. The compound 1-(m-chlorophenyl)-3-(4-dimethylaminobutyl) -2-imidazolinone.

References Cited UNITED STATES PATENTS 2,707,186 4/1955 Du-schinsky260-3096 3,133,079 5/1964 Luckenbaugh 260309.6 3,136,776 6/1964 Stoffel260309.6 3,303,199 2/1967 Doebel et al 260309.6

WALTER A. MODANCE, Primary Examiner.

N. TROUSOF, Assistant Examiner.

1. A COMPOUND SELECTED FROM THOSE OF THE FORMULA: